Epilepsy is one of the most common chronic neurological disorders, and affects approximately 50 million people worldwide. Epilepsy patients have significantly increased morbidity, including closed head injury, fractures, burns, dental injury and soft tissue injury. Decline in or worsening of memory, cognition, depression and sexual function and other lifestyle limitations occur frequently in epilepsy patients. Epilepsy patients also have an increased risk of mortality compared to the general population.
Although various pharmacologic agents are approved to treat epilepsy, many patients are not adequately treated with the currently available options. It is estimated that nearly a third of patients with epilepsy have either intractable or uncontrolled seizures or significant adverse side effects.
Ezogabine or retigabine, also known as ethyl N-[2-amino-4-[(4-fluorophenyl) methylamino]phenyl]carbamate, is an anticonvulsant used as a treatment for partial epilepsies. Ezogabine works primarily as a potassium channel opener, i.e., by activating KCNQ2/3 voltage-gated potassium channels in the brain. Ezogabine was approved by the FDA and is marketed as Potiga™ and Trobalt™. U.S. Pat. No. 5,384,330 and WO 01/01970 describe ezogabine and its use. The most common adverse events with ezogabine are central nervous system effects, particularly dizziness and somnolence. Occasional instances of urinary difficulty may require surveillance. Recently, ezogabine has been associated with skin discoloration and eye pigmentation changes in patients. These more serious side-effects have resulted in the marketing application holders and its removal from the market in 2017.
Because of the beneficial activities seen with ezogabine, there is a continuing interest in developing new compounds to treat epilepsy and other conditions ameliorated by KCNQ2/3 potassium channel opening.